rs61735534

Positions:

• chr15-42359878-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000397163.8(CAPN3):​c.73C>T​(p.His25Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,614,210 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H25H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0081 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00078 (22 hom.)
• Consequence: CAPN3 ENST00000397163.8 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.656

Genes affected

CAPN3 (HGNC:1480): (calpain 3) Calpain, a heterodimer consisting of a large and a small subunit, is a major intracellular protease, although its function has not been well established. This gene encodes a muscle-specific member of the calpain large subunit family that specifically binds to titin. Mutations in this gene are associated with limb-girdle muscular dystrophies type 2A. Alternate promoters and alternative splicing result in multiple transcript variants encoding different isoforms and some variants are ubiquitously expressed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030951798).
• BP6: Variant 15-42359878-C-T is Benign according to our data. Variant chr15-42359878-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 254876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00806 (1228/152342) while in subpopulation AFR AF= 0.0282 (1174/41572). AF 95% confidence interval is 0.0269. There are 14 homozygotes in gnomad4. There are 554 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CAPN3	NM_000070.3	c.73C>T	p.His25Tyr	missense_variant	1/24	ENST00000397163.8	NP_000061.1
CAPN3	NM_024344.2	c.73C>T	p.His25Tyr	missense_variant	1/23		NP_077320.1
CAPN3	NM_173087.2	c.73C>T	p.His25Tyr	missense_variant	1/21		NP_775110.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CAPN3	ENST00000397163.8	c.73C>T	p.His25Tyr	missense_variant	1/24	1	NM_000070.3	ENSP00000380349	P2
CAPN3	ENST00000357568.8	c.73C>T	p.His25Tyr	missense_variant	1/23	1		ENSP00000350181
CAPN3	ENST00000349748.8	c.73C>T	p.His25Tyr	missense_variant	1/21	1		ENSP00000183936
CAPN3	ENST00000318023.11	c.73C>T	p.His25Tyr	missense_variant	1/23	5		ENSP00000326281	A2

Frequencies

GnomAD3 genomes AF: 0.00805 AC: 1226 AN: 152224 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00211 AC: 530 AN: 251040 Hom.: 9 AF XY: 0.00177 AC XY: 240 AN XY: 135830

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000775 AC: 1133 AN: 1461868 Hom.: 22 Cov.: 32 AF XY: 0.000688 AC XY: 500 AN XY: 727232

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00806 AC: 1228 AN: 152342 Hom.: 14 Cov.: 32 AF XY: 0.00744 AC XY: 554 AN XY: 74496

Gnomad4 AFR AF: 0.0282

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00319 Hom.: 3

Bravo AF: 0.00980

ESP6500AA AF: 0.0286 AC: 126

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00268 AC: 325

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2A Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.4
DANN	Benign	0.87
DEOGEN2	Benign	0.0036	T;.;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.89	D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.55	.;N;N;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.18	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.19	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.13, 0.082	.;B;B;B
Vest4		0.17
MVP		0.76
MPC		0.19
ClinPred		0.010	T
GERP RS		4.0
Varity_R		0.041
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61735534; hg19: chr15-42652076;